Entacapone, namely (E)-N,N-diethyl-2-cyano-3-(-3,4-dihydroxy-5-nitrophenyl-)-acrylamide, of formula (I)

is a catechol-O-methyl-transferase (COMT) specific inhibitor, used in combination with levodopa/carbidopa in the treatment of Parkinson's disease, to enhance effectiveness in muscle control.
U.S. Pat. No. 5,446,194 discloses the preparation of entacapone according to the following Scheme 1, which involves the condensation of 3,4-hydroxy-5-nitro-benzaldehyde of formula (II) with N,N-diethylamino-cyano-acetamide of formula (III) in the presence of a catalytic amount of piperidine acetate in dry ethanol.

3,4-Dihydroxy-5-nitrobenzaldehyde of formula (II) is prepared from 5-nitrovanillin by demethylation with hydrobromic acid in acetic acid. Entacapone is marketed as the crystalline form A, with stereochemistry (E), known from U.S. Pat. No. 5,135,950.
According to WO 2005/063693, the preparation disclosed in U.S. Pat. No. 5,446,194 suffers from exceedingly high reaction times, of about 80-100 hours; the reactions do not go to completion and yields are not very good. Furthermore, both intermediate of formula (II) and final product require repeated purifications, due to the high instability of the catechol derivatives, that undergo oxidation when exposed to airs. The intermediate (II) in particular requires specific storage conditions, namely at a temperature of 15° C. in dark rooms.
WO 2005/063693 discloses a novel synthetic alternative to entacapone as shown in the following Scheme 2.

wherein R is methyl or ethyl.
This synthetic route comprises reacting a compound of formula (III) and a compound of formula (IV) in the presence of “mild acid catalysts” (literally), which according to the inventors allow to operate under conditions not aggressive towards the fragile intermediates of formula (IV) and (V). The same reference also reports that intermediate (V) is anyway highly susceptible to hydrolysis even under mild acidic or basic conditions.
However, also this synthetic approach has drawbacks that limit or make the application on an industrial scale difficult. Nitrophenol compounds of formula (IV) and (V) and entacapone itself are indeed poorly stable and the prolonged reflux of the reaction mixture at 105-110° C. involves the formation of pitches in remarkable amounts, which decreases the yield in isolated product and makes purifications of the crude compound necessary.
A further drawback of the prior art are the conditions for entacapone preparation in its crystalline form A. According to U.S. Pat. No. 5,135,950, the crystalline form A is obtained by hot dissolution and subsequent crystallization of the product from an organic acid, e.g. acetic acid, in the presence of strong mineral acids, e.g. hydrobromic acid. Such conditions have the drawback of partly degrading the final product entacapone. Moreover, the product is dried from mixtures containing organic and mineral acids, which involves industrial problems, such as long times necessary to remove the high-boiling solvents and corrosion of the drying apparatus.
WO 2006/064296 solves in part this problem by performing a crystallization from acetone in the presence of considerable amounts of acetic acid. However, the problem of purifying the final product in the presence of a high-boiling organic acid is still unsolved.
There is therefore a need for an industrially applicable process, which provides high yields, makes use of low-cost starting materials and of solvents causing low environmental impaction. Furthermore, in particular as far as the reaction temperature is concerned, the conversion reaction of intermediate of formula (IV) to intermediate of formula (V) should be carried out under milder conditions. Finally, the conditions for the crystallization of the final product should avoid the use of strong acids, high-boiling organic acids and high temperatures.